Carboxyalkyl dipeptides as antiglaucoma agents

ABSTRACT

Methods and pharmaceutical compositions are disclosed for reducing intraocular pressure. The methods and compositions employ an active ingredient which comprises certain benzothiadiazinyl and quinazolinyl substituted carboxyalkyl dipeptides wherein the benzothiadiazinyl or quinazolinyl portions are joined to the dipeptide portions by an aminocarbonyl group.

This application is a divisional application of U.S. Ser. No.07/220,183, filed July 18, 1988, now U.S. Pat. No. 4,906,635, which wasa divisional application of U.S. application Ser. No. 06/903,545, filedon Sept. 3, 1986, now U.S. Pat. No. 4,778,795 which was filed as adivisional application of U.S. application Ser. No. 06/797,104, filedNov. 11, 1985, now U.S. Pat. No. 4,616,102, which was acontinuation-in-part of U.S. application Ser. No. 06/555,311, filed Nov.25, 1983, now U.S. Pat. No. 4,559,340, priority of all of which isclaimed hereunder.

The present invention relates to ophthalmic pharmaceutical compositionscomprising benzothiadiazinyl and quinazolinyl substituted carboxyalkyldipeptides, wherein the benzothiadiazinyl or quinazolinyl portions arejoined to the dipeptide portions by an aminocarbonyl group, and tomethods for using said compositions in the treatment of elevatedintraocular pressure, especially that associated with glaucoma.

BACKGROUND OF THE INVENTION

Glaucoma is an ocular disease complex associated with an elevatedpressure within the eye (i.e., intraocular pressure, IOP). As a resultof the elevated IOP, damage to the optic nerve resulting in irreversibleloss of visual function may ensue. Untreated, this condition mayeventually lead to blindness.

Ocular hypertension, i.e., a condition of elevated intraocular pressurewithout optic nerve damage or characteristic glaucomatous visual fieldloss, is now believed by the majority of ophthalmologists to representthe earliest phase in the onset of glaucoma.

A number of the drugs presently employed to treat glaucoma are notentirely satisfactory, particularly in the earliest course of thedisease when the side effects they produce are often worse than thesymptoms of the disease.

Epinephrine, used as a topical solution, must be utilized cautiously inpatients with high blood pressure, diabetes, hyperthyroidism andcerebral arteriosclerosis due to the possibility of systemic action.

Timolol, a clinically utilized, topically applied agent for loweringIOP, must be used with caution in patients in whom beta-adrenergicblockade may be undesirable. Systemic absorption of topicallyadministered timolol and the resulting systemic betablockade areresponsible for the contraindication of timolol therapy in glaucomapatients with compromised pulmonary function and in patients who cannottolerate its systemic cardiovascular actions.

Pilocarpine, a topical drug, although considered systemically harmlessand quite effective, may cause considerable local difficulties. Pupilconstriction causes the eye to lose its ability to adapt from light todark. Accommodation may become so stimulated that the patient'srefraction is sometimes incorrect and vision becomes blurred. The drugitself may cause a local vasodilation and red eyes. Irritation iscommon.

Carbonic anhydrase inhibitors have been used systemically but they havea number of disadvantages. While effective in lowering intraocularpressure, they often cause a numbness and tingling, gastrointestinalupsets and, frequently, depression, lethargy, a loss of appetite, andgeneral malaise. European Patent Application 81400326.5, Publicationnumber 36,351, attempts to overcome these difficulties by the topicaladministration of an alkali metal salt of a carbonic anhydraseinhibitor.

The present invention provides a new method for reducing and controllingelevated IOP, especially the elevated IOP associated with glaucoma.

SUMMARY OF THE INVENTION

The invention sought to be patented in its pharmaceutical compositionaspect is a topical ophthalmologically acceptable composition useful forreducing and controlling elevated intraocular pressure, especiallyelevated IOP associated with glaucoma, which comprises an intraocularpressure reducing effective amount of a compound of the formulae:##STR1## or their isomers or pharmaceutically acceptable salts thereof,wherein ##STR2## R¹ is hydrogen or lower alkyl; R² and R⁵ areindependently hydrogen, lower alkyl, phenyl, or phenyl(lower)alkyl;

R³ and R⁴ are independently hydrogen, lower alkyl, haloloweralkyl,phenyl, or phenyl(lower)alkyl, or R³ and R⁴ taken together with thecarbon to which they are attached can form a 5-7 membered cycloalkylring;

R⁶ and R⁸ are independently hydroxy, alkoxy having from 1 to 8 carbonatoms, L--Q_(r) --(CH₂)_(s) --O--, wherein L is phenyl, substitutedphenyl, 1- naphthyl or 2-naphthyl; Q is oxygen or sulfur; r is 0 or 1and s is 0 to 4; and wherein the substituents on the phenyl are chosenfrom group M, wherein M is halogen, hydroxy, trifluoromethyl, alkoxyhaving from 1 to 6 carbon atoms, alkyl from 1 to 6 carbon atoms,2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl and phenyl (which phenylgroup may be substituted with halogen, hydroxy, trifluoromethyl, alkoxyhaving from 1 to 6 carbon atoms or alkyl having from 1 to 6 carbonatoms); provided that when s is zero, r is zero; --OCH₂ --OCO--alkylwherein the alkyl has from 3 to 8 carbon atoms, --OCH₂ CO--phenyl,wherein the phenyl may be substituted ##STR3## with group M, 1-gylceryl,or R⁷ is hydrogen, lower alkyl, or aminoloweralkyl;

R⁹ is hydrogen, lower alkyl, unsubstituted or substituted phenyl, andsubstituted or unsubstituted phenyl lower alkyl, wherein phenyl may besubstituted by group M;

R¹⁰ is hydrogen or lower alkyl;

a is 0-8;

b is 1-8:

c is 2-8;

m is 1-4;

n is 0 or 1;

p and q are each 0, 1 or 2, provided that in formulae IIIb and IIIc thesum of p and q is 1 or 2, and that in formula IIId, p is not 0; incombination with an ophthalmologically acceptable carrier for topicaluse. The compounds useful in this pharmaceutical compositions includethose disclosed in Ser. No. 555,311, filed Nov. 25, 1983.

When B is formula IIIb or IIIc, the preferred sum of p and q is 1; whenB is of formula IIId, preferred values for each of p and q are 1.

For compounds of formula I wherein Y is ##STR4## preferred compounds arethose wherein m is 3 or 4. For compounds of formula I wherein Y is##STR5## preferred compounds are those wherein m is 1 or 2. Alsopreferred are compounds wherein R⁷ is hydrogen, methyl or aminobutyl,compounds wherein R¹ and R² are hydrogen or methyl, compounds wherein Xis chlorine, and compounds wherein R⁶ is hydroxy, ethoxy, methoxy,phenoxyethoxy, pivaloyloxymethoxy, or ##STR6## Especially preferred arecompounds wherein both R⁶ and R⁸ are hydroxy.

The invention sought to be patented in its pharmaceutical method aspectis a method for reducing and controlling elevated intraocular pressure,especially that associated with glaucoma, in a mammal such as man, whichmethod comprises administering to said mammal an effective amount of theabove-defined pharmaceutical composition. The method can also employ abeta adrenergic blocking agent or an anti-inflammatory steroid incombination with the composition of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of formulae I and II above can be prepared by the methodsdisclosed in co-pending U.S. application Ser. No. 555,311, filed Nov.25, 1983. The disclosure of which is incorporated herein by referencefor that purpose.

As used herein, "lower alkyl" means straight or branched chainhydrocarbon radicals of from 1 to 6 carbons, e.g. methyl, ethyl, propyl,isopropyl, butyl, t-butyl, pentyl and hexyl. Similarly, "lower alkoxy"means straight or branched alkoxy radicals having 1 to 6 carbon atoms,e.g. methoxy, ethoxy, propoxy, butoxy, iso-butoxy, pentoxy and hexyloxy."Halogen" means fluorine, chlorine and bromine.

Compounds employed in the instant invention include variousstereoisomers and the invention contemplates all such isomers in pureform and admixture. Preferred stereoisomers are those in which theabsolute configuration at each of the three carbon atoms adjacent toboth a nitrogen and a carbonyl group corresponds most closely to theabsolute configuration of L-amino acids.

Examples of suitable compounds for use in the present invention are asfollows:

1-{N-[1(S)-ethoxycarbonyl-5-[2-(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazin-3-yl)acetamido]-pentyl]-(S)-alanyl}-cis, syn-octahydroindole-2(S)-carboxylicacid,

1-{N-[1(S)-carboxy-5[2-(6-chloro-3,4dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazin-3-yl)acetamido]-pentyl]-(S)-alanyl}-cis,syn-octahydroindole-2(S)-carboxylicacid,

1-{N-[1(S)-ethoxycarbonyl-4-[2-(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazin-3-yl)acetamido]-butyl]-(S)-alanyl}-cis,syn-octahydroindole-2(S)-carboxylicacid,

1-{N-[1(S)-carboxy-4-[2-(6-chloro-3,4-sulfamoyl1,2,4-benzothiadiazin-3-yl)acetamido]-butyl]-(S)-alanyl}-cis,syn-octahydroindole-2(S)-carboxylicacid,

1-{N-[1(S)-ethoxycarbonyl-2-(N-(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazin-3-yl-methyl)carbamoyl)ethyl]-(S)-alanyl}-cis,syn-octahydroindole-2(S)-carboxylicacid,

1-{N-[1(S)-carboxy-2-(N-(6-chloro-3,4-dihydro1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazin-3-yl-methyl)-carbamoyl)ethyl]-(S)-alanyl}-cis,syn-octahydroindole-2(S)-carboxylicacid,

1-{N-[1(S)-ethoxycarbonyl-2-(N-(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazin-2-yl-methyl)-carbamoyl)ethyl]-(S)-alanyl)-cis,syn-octahydroindole-2(S)-carboxylic acid,

1-{N-[1(S)-ethoxycarbonyl-2(N-2-(6-chloro-3,4-ethyl)-carbamoyl)ethyl]-(S)-alanyl)-cis,syn-droindole-2(S)-carboxylic acid,

1-(N-[1(S)-carboxy-2-(N-2-(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazin-2-yl-ethyl)-carbamoyl)-ethyl]-(S)-analyl}-cis,syn-octahydroindole-2(S)-carboxylic acid, and

1-{N-[1(S)-carboxy-2(N-(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzthiadiazin-2-yl-methyl)-carbamoyl)-ethyl]-(S)-alanyl}-cis,syn-octahydroindole-2(S)-carboxylic acid.

The compounds employed in this invention form salts with variousinorganic and organic acids and bases which are also within the scope ofthe invention. Such salts include ammonium salts, alkali metal salts,e.g. sodium and potassium salts, and alkaline earth metal salts, e.g.calcium and magnesium salts. Salts with organic and inorganic acids maybe prepared, e.g., HCl, HBr, H₂ SO₄, H₃ PO₄, methanesulfonic acid,toluenesulfonic acid, maleic acid, fumaric acid and camphorsulfonicacid. The non-toxic pharmaceutically acceptable salts are preferred,although other salts are also useful, e.g., in isolating or purifyingthe product. The acid salts (e.g. HCl and maleate) are preferred,especially the maleate.

The salts may be formed by conventional means, as by reacting the freeacid or base forms of the product with one or more equivalents of theappropriate base or acid in a solvent or medium in which the salt isinsoluble, or in a solvent such as water which is then removed in vacuoor by exchanging the cations of an existing salt for another cation on asuitable ion exchange resin.

Ocular hypotensive activity of the compounds of the invention may betested by the procedure described by Watkins et al., J. OcularPharmacol. 1(2): 161-168, 1985.

The compounds employed in the invention are administered in the form ofophthalmic pharmaceutical compositions adapted for topicaladministration to the eye; such as solutions, suspensions, ointments andsolid inserts. Formulations of these compounds may contain from about0.00001 to about 1.0%, preferably 0.00001 to 0.1%, and especially0.00001 to 0.001% of medicament. Other concentrations may be employedprovided the dose is effective in lowering intraocular pressure. As aunit dosage form, between about 0.005 μg to about 0.5 mg, preferably0.005 μg to 50 μg, and especially 0.005 μg to 0.5 μg of the activecompound is applied to the human eye, generally on a daily basis.Individual dosage requirements are variable and must be administered bythe attending clinician on the basis of the severity of the disease andthe condition and response of the patient.

To prepare suitable dosage forms, the active compounds may beconveniently admixed with a non-toxic pharmaceutically acceptablecarrier suitable for topical ophthalmolgic administration. Typical ofsuch pharmaceutically acceptable carriers are, for example, water,mixtures of water and water-miscible solvents such as lower alkanols orvegetable oils, petroleum based jelly, and including also from 0.5 to 5%by weight of hydroxyethyl cellulose, ethyl oleate, carboxymethylcellulose, polyvinylpyrrolidone, and other water solubleophthalmologically acceptable non-toxic polymers, for example, cellulosederivatives such as methyl cellulose, alkali metal carboxymethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,hydroxypropylmethyl cellulose; acrylates such as polyacrylic acidssalts; ethylacrylates; polyacrylamides; natural products such asgelatin, alginates, pectins, tragacanth, karaya, chondrus, agar, acacia;starch derivatives such as starch acetate, hydroxyethyl starch ethers,hydroxypropyl starch; as well as other synthetic derivatives such aspolyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl methyl ether,polyethylene oxide, neutralized carbopol and xanthan gum; and mixturesof these polymers. The pharmaceutical preparation may also containnon-toxic auxiliary substances such as emulsifying, preserving, wetting,bodying agents and the like, as for example, polyethylene glycols 200,300, 400 and 600; carbowaxes 1,000, 1,500, 4,000, 6,000 and 10,000;antibacterial components such as quaternary ammonium compounds;phenylmercuric salts known to have cold sterilizing properties and whichare non-injurious in use; thimerosal; methyl and propyl paraben; benzylalcohol; phenyl ethanol; buffering ingredients such as alkali metalchloride, borate, acetate, gluconate buffers; antioxidants such assodium metabisulfite, butylated hydroxyanisole (BHA), butylatedhydroxytoluene (BHT) and the like; and other conventional ingredientssuch as sorbitan monolaurate, triethanolamine oleate, polyoxyethylenesorbitan monopalmitylate, dioctyl alkali metal sulfosuccinate,monothioglycerol, ethylenediamine tetracetic acid and the like.

Additionally, suitable ophthalmic vehicles can be used as carrier mediafor the present purpose including conventional phosphate buffer vehiclesystems, isotonic boric acid vehicles, isotonic alkali chloridevehicles, tris and the like.

The pharmaceutical preparation may also be in the form of a solidinsert. For example, one may use a solid water soluble polymer as thecarrier for the medicament. Inserts that are known in the art that aresuitable for this use include those described in British Patent 15611,and in U.S. Pat. Nos. 3,993,071; 3,986,510; 3,868,445; and 3,867,510.Solid water insoluble inserts, such as those prepared from ethylenevinyl acetate copolymer, may also be utilized.

The compositions of the invention may include therapeutically effectiveamounts of additional ophthamologically acceptable therapeutic agents inaddition to the compounds of formulae I and II. For example, antibioticsand anesthetics, as well as other IOP-lowering agents may be present.

A particularly advantageous utility for the compounds of this inventionlies in their use in pharmaceutical compositions which also containother compounds known to be useful for the lowering of intraocularpressure. It is contemplated that pharmaceutical compositions containingcompounds of this invention in conjunction with other IOP-loweringcompounds will constitute a more effective and safer therapy than withcompounds containing a single active compound. This effect isparticularly advantageous when the compounds of this invention are usedin combination with beta-adrenergic blockers. For purposes of thepresent invention, the term beta-adrenergic blocker means a compoundwhich by binding to beta-adrenergic plasma membrane receptors reduces oreliminates sympathetic activity or blocks the effects of exogenouslyadministered catecholamines or adrenergic drugs. See, for example,Weiner, N., Drugs that Inhibit Adrenergic Nerves and Block AdrenergicReceptors, in the Pharmaceutical Basis of Therapeutics (ed. A. G.Goodman, L. S. Goodman, A. Gilman), Mcmillan Publishing, New York, 1980,6th ed., pp. 188-197. Examples of preferred beta-adrenergic blockers areatenolol(4-[2-hydroxy-3-[(1-methylethyl)amino]-propoxy]benzeneacetamide),metoprolol (1-[4-(2-methoxyethyl)phenoxy]-3-[(1-methylethyl)amino]-2-propanol), nadolol (5-[3[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,2,3,4-tetrahydro-2,3-naphthalenediol),pindolol (1-(1H-indol-4-yloxy)-3-[(1-methylethyl) amino]-2-propanol),propranolol (1-[(1-methylethyl) amino]-3-(1-naphthalenyloxy)-2-propanol), timolol(1-[(1,1-dimethylethyl)amino]-3-[(4-morpholinyl-1,2,5-thiadiazol-3-yl)oxy]-2-propanol), labetalol (2-hydroxy-5-[1-hydroxy-2-[(1-methyl-3-phenylpropylmethoxy)ethyl]-phenoxy]-3-[(methylethyl)amino]-2-propanol),carteolol(5-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-3,4-dihydro-2(1H)-quinolinone),and dilevalol([R-(R,R)]-2-hydroxy-5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]-benzamide4-methylbenzenesulfonate salt), and pharmaceutically acceptable saltsand isomers thereof.

The usefulness of beta-adrenergic blockers for lowering intraocularpressure is known in the art. For example, the beta-adrenergic blockertimolol is currently approved by the U.S. Food and Drug Administrationfor topical intraocular use for the treatment of glaucoma. It ismarketed in two dose strengths, i.e., 0.25% and 0.5%. As previouslystated, this agent must be used with caution in a defined patientpopulation because of recognized untoward side effects (see PhysiciansDesk Reference for Ophthalmology, 11th edition, 1983, p. 126, MedicalEconomics Co. Inc., Oradell, N.J. 07649).

As one aspect of the present invention, it is contemplated that areduction in intraocular pressure equivalent to that obtained by use ofa beta-blocker, e.g., the approved clinical dose of timolol, may beobtained by use of a lower dose of beta-blocker when such lower dose iscombined with an effective amount of a composition of this inventionsuch as a composition including timolol and 1-{N-[1(S)-carboxy-5[2-(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazin-3-yl)acetamido]-pentyl}-(S)-alanyl)-cis, syn-octahydro-indole-2(S)-carboxylicacid, timolol and1-{N-[1(S)-carboxy-2-(N-(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazin-3-yl-methyl)carbamoyl)ethyl]-(S)-alanyl}-cis,syn-octahydroindole-2(S)-carboxylicacid. It is anticipated that the use of the diminished dosage ofbeta-blocker will result in a reduction of severity and frequency oftimolol-like related side effects.

For purposes of this treatment modality, the preferred ranges of thecomponents of the composition of the invention are as follows:

beta-adrenergic blocker: 50 μg to 250 μg

Compound of formula I or II: 0.025 μg to 5 μg

For purposes of this invention the term "subthreshold intraocularpressure reducing concentration" of the IOP reducing compounds of thisinvention, e.g., 1-{N-[1(S)-carboxy-5[2-(6-chloro-3,4dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazin-3-yl)acetamido]-pentyl]-(S)-alanyl}-cis,syn-octahydro-indole-2(S)-carboxylic acid or1-{N-[1(S)-carboxy-2-(N-6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazin-3-yl-methyl)carbamoyl)ethyl]-(S)-alanyl}-cis,syn-octahydroindole-2(S)-carboxylic acid, means anamount less than the threshold dose, i.e., one drop of 0.001% (w/v).Similarly for example, for purposes of the invention, the term"subthreshold intraocular pressure reducing concentration" of beta-adrenergic blocker, e.g. timolol, means an amount less than thethreshold dose, i.e. one drop of 0.25% (w/v).

Those skilled in the art will appreciate that the "subthresholdintraocular pressure reducing concentration" will consist of a range ofconcentrations (doses), and that there will be a lower limit to saidconcentration below which the present invention will not operate. Forpurposes of this invention, this lower limit or minimum dosage may beconsidered to be about 5% of the effective dose (threshold dose) of theparticular component. The subthreshold intraocular pressure reducingconcentration that is actually utilized, whether for compositionaccording to this invention or for a particular beta-adrenergic blockerwill depend on, inter alia, the potency of each particular IOP reducingcompound, the combination being administered and the age, size andcondition of the patient being treated, as well as on the severity ofthe disease state.

Those skilled in the art will know that a particular dosage of activeingredient may be calculated if one assumes that one drop of solution isbeing administered and if one knows the concentration (w/v) of theparticular solution that is being administered. Thus, one drop (1/20 ml)of a 0.25% solution (contains 2.5 mg of active per ml) is known tocontain 0.125 mg or 125 μg of active.

It is also comtemplated that a concentration of the inventivecomposition which is subthreshold for lowering IOP, when combined with aconcentration of beta-adrenergic blocker which is also subthreshold forlowering IOP, will result in significant IOP-lowering. The clinicalimplication of such a result is that a combination of the two drugs willprovide a clinically significant lowering of IOP with limited sideeffect liability, e.g., bradycardia and bronchoconstriction which occurwith IOP-lowering effective concentrations of beta-adrenergic blockers.

For purposes of this treatment modality, the preferred ranges of thecomponents of the composition of the invention are as follows:

beta-adrenergic blocker: from 5 μg to 125 μg

Compound of formula I or II: 0.005 μg to 1 μg

Another advantageous clinical characteristic of thisbeta-blocker/compound of formula I or II combination is that the maximumlowering of IOP attainable from monotherapy with a beta-adrenergicblocker (e.g. timolol) can be significantly increased when combined withsubthreshold concentrations of a compound of formula I or II. Theclinical implication of these findings is that in patients whoseelevated IOP (e.g. glaucoma) is not adequately controlled by maximumrecommended concentrations of standard therapy, e.g., timolol, that suchpatients could be treated with the combination of compounds to achievegreater lowering of IOP than that attainable by either treatment alone.Such treatment would result in greater clinical benefit with no increasein side effects.

For purposes of this treatment modality, the preferred ranges of thecomponents of the composition of the invention are as follows:

beta-adrenergic blocker: from 25 μg to 500 μg

Compound of formula I or II: 0.005 μg to 1 μg

The IOP-lowering effects of these combinations of the invention may bemeasured by the procedure described in the Watkins et al. article citedabove.

The pharmaceutical compositions of the invention (compounds of formula Ior II/beta-adrenergic blockers) are administered in the form ofophthalmic pharmaceutical compositions adapted for topicaladministration to the eye; such as solutions, suspensions, ointments andsolid inserts. Formulations of the invention may contain the followingamounts of each constituent:

Substituted carboxyalkyl dipeptides of formula I or II from 0.00001 to0.1% (w/v) and especially 0.001 to 0.01% of medicament. As a unit dosageform, an amount of from between 0.005 μg to 50 μg, preferably 0.05 μg to10 μg., and especially 0.5 μg to 5 μg of the active composition isapplied to the human eye. Especially preferred are1-{N-[1(S)-carboxy-5[2-(6-chloro-3,4 dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazin-3-yl)acetamido]-pentyl]-(S)-alanyl}-cis,syn-octahydroindole-2(S)-carboxylicacid and 1-(N-[1(S)-ethoxycarbonyl-2-(N-(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazin-3-yl-methyl)carbamoyl)ethyl]-(S)-alanyl}-cis,syn-octahydroindole-2(S)-carboxylicacid and 1-{N-[1(S)-carboxy-2-(N-(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazin-3-yl-methyl)carbamoyl)ethyl]-(S)-alanyl}-cis,syn-octahydroindole-2(S)-carboxylicacid.

Beta-adrenergic blocker from 0.001 to 1% (w/v) and especially 0.01 to0.5% of medicament. As a unit dosage form, an amount of beta-adrenergicblocker from between 0.5 μg to 500 μg and preferably 5 μg to 250 μg. ofthe active composition is applied to the human eye. Other concentrationsmay be employed provided the dose is effective in lowering intraocularpressure. Individual dosage requirements, i.e. the amount of each doseand the frequency of administration, will depend on the severity of thedisease and the response of the patient.

In one embodiment of the method of the invention, it is anticipated thatboth active ingredients, i.e., compound of formula I or II andbeta-blockers, will be administered simultaneously and be contained inone pharmaceutical dosage form. Each component being present in thedosage form in its own respective preferred concentration.

Suitable dosage forms for the pharmaceutical compositions comprising thesubstituted carboxyalkyl dipeptides and beta-adrenergic blockers may beconveniently admixed with compatible non-toxic pharmaceuticallyacceptable carriers suitable for topic ophthalmolgic administration suchas those described supra.

We also contemplate that the elevation in IOP associated with theclinical ophthalmic and systemic use of anti-inflammatory steroids canbe reduced by the administration of a composition of the presentinvention. In particular, an increase in IOP is most often associatedwith the ophthalmic administration of steroidal anti-inflammatory agentsand may produce intractable glaucoma in some susceptible individuals.Anti-inflammatory steroids include, but are not limited to,hydrocortisone, cortisone, prednisolone, prednisone, dexamethasone,methylprednisolone, triamcinolone, betamethasone, alclometasone,flunisolide, beclomethasone, clorocortolone, diflorasone, halcinonide,fluocinonide, flucinolone, desoximetasone, medrysone, paramethasone,9,21-dichloro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16α-methyl-pregna-1,4-diene-3,20-dione andfluorometholone, and their pharmaceutically acceptable salts and esters.Preferred steroids are hydrocortisone, prednisolone, dexamethasone,betamethasone, beclomethasone, medrysone and fluoromethalone and theirpharmaceutically acceptable salts and esters. This rise in IOP may occurwith all modes of administration of the drugs, including systemic(usually oral), local injection (e.g., depot injection), and especiallywith ophthalmic topical or intravitreal administration. The compositionof the invention may be administered following steroid treatment tolower elevated IOP, or may be co-administered with the steroid tosuppress the IOP-raising effect of the steroid while not interferingwith the anti-inflammatory activity of the steroid.

It is further contemplated that any possible combination of dosage formsmay be used to administer the combination, e.g., oral steroid/topicalcomposition of the invention, topical steroid/oral composition of theinvention, oral steroid/oral composition of the invention, topicalsteroid/topical composition of the invention, and locally injectedsteroid/topical composition of the invention, although a preferredcombination comprises a steroid and a topical composition of theinvention. For ophthalmic use, a combination of a topical steroid and atopical composition of the invention is preferred. More preferred is atopical ophthalmic pharmaceutical dosage form comprising both a steroidand compound of formula I or II. Such compositions or combinations canbe employed in a method for reducing and controlling the elevated IOPassociated with ophthalmic and systemic use of steroidalanti-inflammatory agents, which method comprises administering to amammal effective amounts of a steroid and a compound of formula I or II,either separately or in the same pharmaceutical composition.

Since the present invention relates to treatment with a combination of acomposition of the invention and a sterodial anti-inflammatory agentwherein the composition of the invention and steroid may be administeredseparately, the invention also relates to combining separatepharmaceutical compositions in kit form, that is, combining two separateunits, a composition of the invention including a compound of formula Ior II and an anti-inflammatory steroid pharmaceutical composition, in asingle package. Preferred components of the kit comprise a topicalophthamological pharmaceutical composition containing a compound offormula I or II as defined above and a pharmaceutically acceptableanti-inflammatory steroid composition. More preferred components of thekit are a topical ophthamological pharmaceutical composition containinga compound of formula I or II and a topical ophthamologicalanti-inflammatory steroid pharmaceutical composition. A particularadvantage of the more preferred embodiment of the kit resides in theability to provide a combination of a composition of the invention whichcan be administered one or twice a day and a steroidal composition whichmay be administered as frequently as once each hour.

While the mechanism by which corticosteroids provide anti-inflammatoryactivity is unknown, their ability to provide relief from inflammatorysymptoms is widely recognized. See, for example, Haynes, R. C., Jr., andMurad, F., "Adrenocorticotropic Hormone; Adrenocortical Steroids andTheir Synthetic Analogs, Inhibitors of Adrenocortical SteroidBiosynthesis" in The Pharmacological Basis of Theraputics (ed., A. G.Gilman, L. S. Goodman, A. Gilman), Macmillan Publishing, New York, 1980,6th ed., pp. 1470-1492, n.b. pg. 1490-1491.

In this combination treatment modality, topical formulations of theinvention may combine the following amounts of each compound of formulaI or II and steroidal constituent, or each constituent may beadministered separately:

Compound of formula I or II: from about 0.00001 to about 1.0% (w/v) andespecially about 0.0001 to about 0.01% of medicament. As a unit dosageform, an amount of a compound of formula I or II from between about0.005 μg to about 500 μg, preferably about 0.005 μg to about 50 μg, andespecially 0.005 μg to 5 μg of the active component is applied to thehuman eye. Individual dosage requirements, i.e., the amount of each doseand the frequency of administration, will depend on the particularpotency of the compound selected, the severity of the increase in IOPand the response of the patient.

Steroid from about 0.05 to about 1.5% (w/v) of medicament. As a unitdosage form, an amount of steroid from between 20 μg to 600 μg of theactive composition is applied to the human eye. Individual dosagerequirements, i.e., the amount of each dose and the frequency ofadministration will depend on the potency of the particular steroid, theseverity of the disease and the response of the patient. Approximateranges for such steroids are well known to those skilled in the art. Theparticular steroid employed will determine which compound of formula Ior II and concentration thereof to select for use in a combinationpreparation.

In the preferred method of the invention, both active ingredients, i.e.,compound of formula I or II and steroid, will be administeredsimultaneously and be contained in one pharmaceutical dosage form, eachcomponent being present in the dosage form in its own respectivepreferred concentration. When the steroid is administered systemicallyor topically other than in an ophthalmological composition, theconcentration of the steroid in the composition and the unit dosageweight may vary considerably, depending as above on such factors as thepotency of the steroid, its onset and duration of action as well as theseverity of the disease, and the response of the patient. Appropriatedosage ranges for systemic and topical administration of each steroidare well known in the art.

Those skilled in the art will know that for solutions and suspensions, aparticular dosage of active ingredient may be calculated if one assumesthat one drop of solution is being administered and if one knows theconcentration (w/v) of the particular solution that is beingadministered. Thus, one drop (1/20 ml) of a 0.25% solution (contains 2.5mg of active per ml) is known to contain 0.125 mg or 125 μg of active.

Where utilized herein, the term "controlling the elevated intraocularpressure" means the regulation, attenuation and modulation of increasedintraocular tension, e.g., the primary diagnostic symptom of thedisease, glaucoma. The term also means that the diminution, in theotherwise elevated intraocular pressure, obtained by the practice of theinvention is maintained for a significant period of time as, forexample, between consecutive doses of the composition of the invention.

The following examples further illustrate the compositions of theinvention and the preparation of compounds employed in the presentinvention.

EXAMPLE 1 1-{N-[1(S)-Ethoxycarbonyl-5-[2-(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazin-3-yl)acetamido]pentyl]-(S)-alany}-cis, syn-octahydroindole-2(S)-carboxylicacid.

A. Combine 3-ethoxycarbonylmethyl-6-chloro-7-sulfamoyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (7.7 g) with ethanol (EtOH)(250 ml) and 1N sodium hydroxide (NaOH) (70 ml) for 4 hours. Concentrateto 50 ml, add 1N hydrochloric acid (HCl) (70 ml), and extract with ethylacetate (EtOAc). Dry the EtOAc extract over anhydrous magnesium sulfateand concentrate to obtain3-carboxymethyl-6-chloro-7-sulfamoyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide.

B. Combine the product of part A (6.0 g),6-amino2-(1(S)-t-butyloxycarbonylethylamino)hexanoic acid ethylester(5.1 g), and N-hydroxy benzotriazole hydrate (2.6 g) with drydimethylformamide (DMF) (150 ml) at 0° C. Add1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (DCI) (3.2g). After 3 hours, concentrate the resultant solution and partitionbetween EtOAc and 1N sodium bicarbonate (NaHCO3). Dry and concentratethe organic layer to obtain a crude oil (12.5 g), which can be furtherpurified by chromatography on silica gel usingchloroform:methanol:ammonia (90:9:1) to obtainN-5(S)-ethoxycarbonyl-5-[1(S)-(t-butyloxycarbonyl) ethylamino]pentyl-6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazine-3-acetamide.

C. Combine the product of step B (8.9 g) with HCl saturated dioxane (400ml) for 24 hours. Decant the solution from the oil and dry the oil invacuo to obtain N-(5(S)-ethoxycarbonyl-5-[1(S)-carboxyethylamino]-pentyl-6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-b 1,2,4-benzothiadiazine-3-acetamide hydrochloride.

D. Combine the product of part C (5.8 g), triethyl-amine (1.8 g),2(S)-benzyloxycarbonyl-(S),(S) perhydroindole (2.4 g), andN-hydroxybenzotriazole. H₂ O (1.4 g) in dry dimethylformamide (100 ml)at 0° C., then add DCI (1.7 g). After 2 hours, concentrate and partitionbetween EtOAc and 1N NaHCO₃. Dry the organic layer and evaporate thesolvent in vacuo. Chromatograph the resultant residue on silica gel,eluting with chloroform:methanol:ammonia (90:9:1) to obtain1-N-[1(S)-ethoxycarbonyl)-5-[2-(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazin-3-yl)acetamido]pentyl]-(S)-alanyl-2(S)-benzyloxycarbonyl-cis,syn-octahydroindole.

E. Combine the product of part D (2.2 g) with 20% hydrogen bromide inacetic acid (50 ml) and stir 4 hours at room temperature (R.T.)Concentrate the resultant mixture, treat with diethyl ether and filterto obtain a crude solid. Chromatograph the resultant solid on AG-50W-X2resin (hydrogen form), using 3% pyridine as eluant. Lyophilize eluatefractions to obtain a solid, and chromatograph the solid on sephadex,eluting with methanol to obtain the title compound, [α]_(D) ²⁶ 32 -25.6°(ethanol, C=0.5).

EXAMPLE 2 1-{N-[1(S)-Carboxy-5-[2-(6-chloro-3, 4-dihydro-1-1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazin-3-yl)acetamido]pentyl]-(S)-alanyl}-cis, syn-octahydroindole-2(S)-carboxylicacid.

Combine the product of part D of Example 1 (1.8 g) with 1N NaOH (10.8ml) and allow to stand 16 hours. Add 1N HCl (10.8 ml) to the resultantsolution and filter the solid which precipitates to obtain the titlecompound, m.p. 205-209° C.

EXAMPLE 3 1-{N-[1(S)-Ethoxycarbonyl-4-[2-(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazin-3-yl)-acetamido]]butyl]-(S)-alanyl}-cis, syn-octahydroindole-2(S)-carboxylic acid,hydrochloride.

A. Dissolve N -carbobenzyloxy-(S)-ornithine, ethyl ester (49.5 g)t-butyl α-bromopropionate (75 g) and triethylamine (75 ml) in DMF (400ml), and heat this solution at 80° for 18 hours. Cool the reactionmixture, add water (2000 ml) and extract with ether (4×400 ml). Dry theorganic layer over MgSO4 and concentrate the dried ether solution invacuo. Chromatograph the resultant residue (20 g portions) on WatersPrep 500 using 4 cartridges and hexane:EtOAc (3:1) as eluant to giveN-[1(S)-ethoxycarbonyl-4-(benzyloxy-carbonylamino)-butyl]-(S)-alanine,t-butyl ester and the corresponding (R)-alanine isomer.

B. Dissolve the product of step A (23.32 g) in absolute ethanol (200 ml)and water (200 ml). Add 10% palladium on charcoal (7.0 g). Hydrogenateat 50 psi for 3 hours. Filter and concentrate in vacuo to giveN-[1(S)-ethoxycarbonyl-4-aminobutyl]-(S)-alanine, t-butyl ester (useimmediately in next step). C. Dissolve the product of step B (15.23 g),3-carboxymethyl-6-chloro-3,4-dihydro-7-sulfamoyl-1,2,4-benzothiadiazine-1,1-dioxide (19.6 g), DCI (10.83 g) and1-hydroxybenzotriazole (8.45 g) in DMF (150 ml) and stir at roomtemperature for 18 hours. Concentrate the reaction mixture at roomtemperature, add dichloromethane and concentrate. Partition theresultant residue between EtOAc and 1N NaHCO3. Dry the organic layer onMgSO4 and concentrate in vacuo. Chromatograph the resultant residue onsilica gel (2 cartridges) using EtOAc as eluant on the Waters Prep 500to give N-1(S)-ethoxy-carbonyl-4-[2-(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazin-3-yl)acetamido]butyl-(S)-alanine, t-butyl ester.

D. Treat the product of step C (11.0 g) with dioxane saturated with HClgas (100 ml) and stir at room temperature for 18 hours. Concentrate invacuo and triturate the residue with ether to giveN-1(S)-ethoxy-carbonyl-4-[2-(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazin-3-yl)acetamido]butyl-(S)-alanine hydrochloride.

E. Treat the product of step D (6.26 g) with cis,syn-octahydroindole-2(S)-carboxylic acid benzyl ester (2.15 g),N-methylmorpholine (1.86 ml), 1-hydroxybenzo-triazole (1.30 g) and DCI(2.49 g) in DMF (12 ml) at room temperature for 18 hours. Concentratethe resultant mixture in vacuo at room temperature. Add water andextract with EtOAc. Concentrate the dried (MgSO4) organic solution invacuo at room temperature. Chromatograph the resultant residue on silicagel (1 kg. 60-200 mesh) using EtOAc:absEtOH (9:1) as eluant to obtain1-[1(S)-ethoxycarbonyl-4-[2-(6-chloro-3,4-dihydro-b 1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazin-3-yl)acetamido]butyl]-(S)-alanyl -cis, syn-octahydroindole-2(S)-carboxylicacid, benzyl ester.

F. To the benzyl ester of step E, add cold 20% HBr in glacial aceticacid (20 ml), warm to room temperature and stir for 5 hours. Concentratethe reaction mixture in vacuo and triturate the residue with ether togive the corresponding hydrobromide salt.

G. Absorb the product of step F (0.70 g) on a strongly acidic ionexchange column (Bio-Rad AG 50W-X2) and elute with abs, EtOH:H₂ O (1:4)and then with abs EtOH:H₂ O:pyridine (77:19:4). Concentrate the desiredfractions as determined by thin layer chromatography (desired product ispositive to iodine). Obtain the HCl salt by adding the resultant residueto dichloromethane containing HCl gas and concentrate the resultingmixture. Chromatograph the resultant residue (20 g) on a sephadex column(170 g) using methanol as eluant to give the title compound, a whitesolid [α]_(D) ²⁶ -23.2° (MeOH).

EXAMPLE 4 1-{N-1(S)-carboxy-4-[2-(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazin-3-yl)-acetamido]butyl]-(S)-alanyl}-cis, syn-octahydroindole- 2(S)-carboxylicacid hydrochloride.

To the product from Example 3 step F (0.76 g) at 0.5°, add 0.5 NaOH (15ml), warm to room temperature (1/2 hour) and stir at room temperaturefor 18 hours. Concentrate the reaction mixture in vacuo. Treat theresultant residue in the manner described in Example 3, step G to obtainthe title compound, [α]_(D) ²⁶ =-16.6° (MeOH).

EXAMPLE 5 1-(N-[1(S)-Ethoxycarbonyl-2-(N-(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-l,2,4-benzothiadiazin-3-yl-methyl)-carbamoyl)ethyl]-(S)-alanyl)-cis, syn octahydroindole-2(S)-carboxylicacid.

A. Combine3-aminomethyl-6-chloro-7-sulfamoyl-3,4-dihydro-benzothiadiazine-1,1-dioxidehydrochloride (1.09 g), triethylamine (0.31 g), hydroxybenzotriazolehydrate (0.46 g), and N-(t-butoxycarbonyl)-(S)-aspartic acid, α-ethylester in dry DMF (20 ml). Add DCI (0.64 g) and stir 1.5 hours. Partitionthe resultant mixture between water and EtOAc. Wash the organic layerwith water, 1.0N NaHCO₃, then brine. Dry the organic layer over MgSO₄and concentrate. Crystallize the resultant residue from CHCl₃ -CH₃ OH toobtain N-(t-butoxycarbonyl-(S)-aspartic acid, α-ethyl ester,β-(6-chloro-7-sulfamoyl-3,4-dihydro-1,1-dioxo-1,2,4-benzothiadiazine-3-methylamide),m.p. 173° (dec).

B. Combine the product of step A (1.14 g) with 6M HCl/dioxane (10 ml).Stir 15 minutes, decant the solution, and stir the residue with ether.Filter to obtain (S)-aspartic acid, α-ethyl ester,β-(6-chloro-7-sulfamoyl-3,4-dihydro-1,1-dioxo-1,2,4-benzothiadiazine-3-methylamide) hydrochloride.

C. To the product of step B (0.91 g) and triethylamine (0.26 g) in EtOAc(20 ml), add a solution of t-butyl2R-(trifluoromethanesulfonyloxy)propionate (0.71 g) in EtOAc (5 ml).Stir 3 hours and wash with water, 5% citric acid, 5% NaHCO₃, then brine.Dry the organic layer over MgSO₄ and concentrate. Chromatograph theresultant residue on silica gel eluting with 1% MeOH/EtOAc to obtainN-(1(S)-t-butoxycarbonylethyl)-(S)-aspartic acid, α-ethyl ester,β-(6-chloro-7-sulfamoyl-3,4-dihydro-1,1-dioxo-1,2,4-benzothiadiazine-3-methylamide),[α]_(D) ²⁶ =-19.4° (EtOH, C=0.5).

D. Combine the product of step C (0.90 g) with 10 ml 6M HCl/dioxene andanisole (1.6 g). Let stand 24 hours and decant the solution. Trituratewith ether and filter to obtain N-(1(S)-carboxyethyl)-(S)-aspartic acid,α-ethyl ester,β-(6-chloro-7-sulfamoyl-3,4-dihydro-1,1-dioxo-1,2,4-benzothiadiazine-3-methylamide)hydrochloride.

E. To the product of step D (0.58 g), triethylamine (0.20 g),hydroxybenzotriazole hydrate (0.15 g) and benzyl(S),(S),(S)-perhydroindole-2-carboxylate (0.26g) in dry DMF (10 ml), addDCI (0.,19 g). After 2 hours, concentrate and partition between EtOAcand 1N NaHCO₃. Wash with water, then brine. Dry the organic layer overMgSO₄ and concentrate. Chromatograph the resulting residue on silica gelwith EtOAc to obtain two isomers of benzyl1-{N-[1(S)-ethoxycarbonyl-2-(N-(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazin-3-yl-methyl)carbamoyl)-ethyl]-(S)-alanyl}cis, syn-octahydroindole-2(S)carboxylate,(less polar isomer A, [α]_(D) ²⁶ =+4.1°, more polar isomer B, [α]_(D) ²⁶=-82.2.°).

F. Hydrogenate separately each isomer (0.4 g) prepared in Step E inethanol (70 ml) with 0.4 g 10% Pd/C at 1 atm. until uptake of 0.5 mmolehydrogen. Filter and concentrate the filtrate to obtain the titlecompound as a solid. Isomer A, [α]²⁶ _(D) =+28.4° (ethanol, c=1). IsomerB, [α]_(D) ²⁶ =-69.3° (ethanol, c=1).

EXAMPLE 6 1-{N-[1(S)-Carboxy-2-(N-(6-chloro-3,4-dihydro-1,1,-dioxo-7-sulfamoyl-1,2,4-benzothiadiazin-3-YL-methyl)-carbamoyl)ethyl]-(S)-alanyl)-cis,syn-octahydroindole-2(S)-carboxylic acid

Following the procedure of Example 4, convert each isomer (A and B) ofthe product of Example 5 to the corresponding isomer of the titlecompound. Isomer A, [α]_(D) ²⁶ =-12.7°. Isomer B, [α]_(D) ²⁶ =-20.0°.

EXAMPLE 7 1-{N-[1(S)-Ethoxycarbonyl-5-(N-(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazin-2-yl)acetamido)-pentyl]-S-alanyl)-cis, syn-octahydroindole-2(S)-carboxylicacid.

A. To 6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazine(6.0 g) in dry DMF (50 ml). Add Cs₂ CO₃ (3.26 g=10 mmol) and benzylbromoacetate (4.58 g) and stir 18 hours. Pour into water, extract withethyl acetate, and wash with water. Dry the organic layer over MgSO4 andconcentrate. Chromatograph the resultant residue on silica gel with 10:1CHCl₃ -MeOH to obtain benzyl(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiazin-2-yl)acetate.

B. Combine the product of step A (0.44 g) with 0.07 g 10% Pd/C in THF(50 ml). Hydrogenate at 1 atm until uptake of 1.0 eq. hydrogen. Filterand concentrate the filtrate to obtain(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazin-2-yl)acetic acid as a foam.

C. Treat the product of step B in a manner similar to that described inExample 1, step B to obtain the corresponding1,2,4-benzothiadiazin-2-acetamide.

D. Treat the product of step C in a manner similar to that described inExample 1, step C to obtain the corresponding hydrochloride.

E. Treat the product of step D in a manner similar to that described inExample 1, step D to obtain1-{N-[1(S)-ethoxycarbonyl)-5-[N-(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazin-2-yl)acetamido]pentyl]-(S)-alanyl}-2(S)-benzyloxycarbonyl-cis,syn-octahydroindole.

F. Treat the product of step E with HBr as described in Example 1 step Eto obtain the title compound.

EXAMPLE 8 1-{N-[1(S)-ethoxycarbonyl-2-(N-2-(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiazin-2-yl)ethyl)carbamoyl-ethyl]-(S)-alanyl)-cis,syn-octahydroindole-2S-carboxylic acid.

A. Treat6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazine withCs₂ CO₃ and substitute 1,2-dibromoethane for benzylbromoacetate in theprocedure of Example 7, step A to obtain2-(2-bromoethyl)-6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazine.

B. Combine the product of step A (12.2 g) with sodium azide (3.9 g) inDMF (200 ml). Stir 44 hours, extract with ethyl acetate, wash withwater, dry the organic layer over MgSO₄ and concentrate. Dissolve theresultant residue in ethanol (150 ml), add 5.0 g 10% Pd/C andhydrogenate at 3 atm for 4 hours. Filter and concentrate the filtrate toobtain 2-(2-aminoethyl)-6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazine.

C. Treat the product of step B with N-(t-butoxy-carbonyl)-(S)-asparticacid, α-ethyl ester as described in Example 5, step A, and continue theprocedure described in Example 5, steps B through F to obtain the titlecompound.

Using the methods described above and substituting appropriate reagents,the compounds described in the following tables are prepared.

                                      TABLE 1                                     __________________________________________________________________________    FORMULA I                                                                      ##STR7##                                                                     A  B  P q n Y             X  R.sup.1                                                                            R.sup.2                                                                             R.sup.6                                                                              R.sup.7                                                                              R.sup.8                                                                              m                __________________________________________________________________________    SO.sub.2                                                                         IIIa                                                                             --                                                                              --                                                                              --                                                                              (CH.sub.2).sub.2 CONH                                                                       CF.sub.3                                                                         CH.sub.3                                                                           H     OCH.sub.2 CH.sub.3                                                                   CH.sub.3                                                                             OH     4                SO.sub.2                                                                         IIIc                                                                             1 1 --                                                                              CH.sub.2 CON(CH.sub.3)                                                                      Cl H    CH.sub.3                                                                            OH     H      OH     3                SO.sub.2                                                                         IIId                                                                             1 1 0 CH.sub.2 CONH Cl CH.sub.3                                                                           H     OCH.sub.2 CH.sub.3                                                                   CH.sub.3                                                                             OH     4                SO.sub.2                                                                         IIIa                                                                             --                                                                              --                                                                              --                                                                               CH.sub.2 NHCO                                                                              Cl H    H     OCH.sub.3                                                                            CH.sub.3                                                                             OCH.sub.3                                                                            3                SO.sub.2                                                                         IIIc                                                                             1 1 --                                                                              CH.sub.2N(CH.sub.3)CO                                                                       CF.sub.3                                                                         H    φ OH     CH.sub.3                                                                             OH     4                SO.sub.2                                                                         IIId                                                                             1 1 0 (CH.sub.2).sub.3 NHCO                                                                       Cl CH.sub.2 CH.sub.3                                                                  CH.sub.2 CH.sub.3                                                                   OH     (CH.sub.2).sub.4 NH.sub.2                                                            OH     3                CO IIIa                                                                             --                                                                              --                                                                              --                                                                              CONH          Cl CH.sub.3                                                                           H     OCH.sub.2 CH.sub.3                                                                   CH.sub.3                                                                             OH     3                CO IIIb                                                                             0 1 --                                                                              CON(CH.sub.3) CF.sub.3                                                                         H    CH.sub.2 φ                                                                      OH     (CH.sub.2).sub.4 NH.sub.2                                                            OH     2                CO IIIc                                                                             0 1 --                                                                              (CH.sub.2).sub.4 CON(φ)                                                                 Cl CH.sub.3                                                                           CH.sub.3                                                                            OH     CH.sub.3                                                                             OH     2                CO IIId                                                                             1 1 0 (CH.sub.2).sub.2 CON(CH.sub.2 φ)                                                        CF.sub.3                                                                         CH.sub.2 CH.sub.3                                                                  H     OCH.sub.2 CH.sub.3                                                                   CH.sub.3                                                                             OCH.sub.3                                                                            4                CO IIIa                                                                             --                                                                              --                                                                              --                                                                              CH.sub.2 NHCO Cl H    φ OH     CH.sub.2 CH.sub.3                                                                    OH     1                CO IIIb                                                                             0 1 --                                                                              (CH.sub.2).sub.4 N(CH.sub.2 φ)CO                                                        Cl CH.sub.3                                                                           H     OH     CH.sub.3                                                                             OCH.sub.2 CH.sub.3                                                                   3                CO IIIc                                                                             1 1 --                                                                              (CH.sub.2).sub.2 NφCO                                                                   CF.sub.3                                                                         CH.sub.3                                                                           CH.sub.3                                                                            OCH.sub.2 CH.sub.3                                                                   (CH.sub.2).sub.3 NH.sub.2                                                            OH     4                CO IIId                                                                             1 1 0 (CH.sub.2)N(CH.sub.3)CO                                                                     Cl CH.sub.3                                                                           CH.sub.3                                                                            OH     H      OH     1                SO.sub.2                                                                         IIIb                                                                             1 0 --                                                                              CH.sub.2 CONH Cl H    H     OH     CH.sub.3                                                                             OH     1                SO.sub.2                                                                         IIIb                                                                             1 1 --                                                                              CH.sub.2 N(φ)CO                                                                         Cl CH.sub.3                                                                           CH.sub.3                                                                            OCH.sub.2 CH.sub.3                                                                   CH.sub.3                                                                             OH     4                CO IIIb                                                                             2 0 --                                                                              (CH.sub.2).sub.2 CON(CH.sub.3)                                                              CF.sub.3                                                                         H    H     OH     CH.sub.3                                                                             OH     3                CO IIIb                                                                             0 2 --                                                                              (CH.sub.2).sub.6 NHCO                                                                       Cl CH.sub.3                                                                           CH.sub.3                                                                            OH     H      OH     1                SO.sub.2                                                                         IIIc                                                                             1 0 --                                                                              (CH.sub.2).sub.3 CON(CH.sub.2 φ)                                                        Cl H    CH.sub.3                                                                            OH     CH.sub.3                                                                             OH     3                SO.sub.2                                                                         IIIc                                                                             1 1 --                                                                              CH.sub.2 N(CH.sub.3)CO                                                                      CF.sub.3                                                                         H    H     OCH.sub.2 CH.sub.3                                                                   (CH.sub.2).sub.4 NH.sub.2                                                            OH     4                CO IIIc                                                                             2 0 --                                                                              CONH          Cl CH.sub.3                                                                           CH.sub.3                                                                            OH     CH.sub.3                                                                             OH     3                CO IIIc                                                                             0 2 --                                                                              (CH.sub.2).sub.4 N(CH.sub.3)CO                                                              Cl H    H     OH     H      OH     2                SO.sub.2                                                                         IIId                                                                             1 0 0 (CH.sub.2).sub.6 CON(CH.sub.2 φ)                                                        Cl CH.sub.3                                                                           CH.sub.2 φ                                                                      OH     CH.sub.3                                                                             OH     4                SO.sub.2                                                                         IIId                                                                             1 0 1 CH.sub.2 NHCO Cl H    H     OH     H      OH     1                CO IIId                                                                             2 0 0 CH.sub.2 NHCO Cl H    H     OCH.sub.3                                                                            CH.sub.3                                                                             OH     3                CO IIId                                                                             2 0 1 CONH          Cl H    H     OH     CH.sub.2 CH.sub.3                                                                    OH     4                __________________________________________________________________________

    TABLE 2      FORMULA II      ##STR8##      A B p q n % X R.sup.1 R.sup.3,R.sup.4 R.sup.6 R.sup.7 R.sup.8 m      SO.sub.2 IIIa -- -- -- (CH.sub.2).sub.2 CON(CH.sub.3) Cl CH.sub.3     H,CH.sub.3 OH CH.sub.3 OH 3 SO.sub.2 IIIc 1 1 -- CH.sub.2 CON(φ) Cl     H CH.sub.3,CH.sub.3 OCH.sub.2 CH.sub.3 H OCH.sub.2 CH.sub.3 4 SO.sub.2     IIId 1 1 0 (CH.sub.2).sub.6 CON(CH.sub.3 φ) Cl CH.sub.2 CH.sub. 3     H,φ OCH.sub.3 (CH.sub.3).sub.4 NH.sub.2 OH 2 SO.sub.2 IIIa -- -- --     (CH.sub.2).sub.2 N(CH.sub.2 CH.sub.3)CO CF.sub.3 H H,CH.sub.2 φ OH     CH.sub.3 OH 4 SO.sub.2 IIIc 1 1 -- (CH.sub.2).sub.2 N.sub.φ CO Cl H     H,H OH CH.sub.2 CH.sub.3 OCH.sub.2 CH.sub.3 1 SO.sub.2 IIId 1 1 0     (CH.sub.2).sub.3 N(CH.sub.2 CH.sub.2 φ)CO Cl CH.sub.3 H,H OCH.sub.2     CH.sub.2 CH.sub.3 OH 4 CO IIIa -- -- -- (CH.sub.2).sub.2 NHCO Cl     CH.sub.3 (CH.sub.2).sub.4 OH CH.sub.3 OH 4 CO IIIb 0 1 -- (CH.sub.2).sub.     3 N(φ)CO Cl CH.sub.2      CH.sub.3 H,H OH H OH 3 CO IIIc 0 1 -- (CH.sub.2).sub.2 N(CH.sub.2     φ)CO Cl H H,CH.sub.3 OCH.sub.2 CH.sub.3 (CH.sub.2).sub.4 NH.sub.4     OCH.sub.3 2 CO IIId 1 1 0 (CH.sub.2).sub.6 N(CH.sub.2 CH.sub.2      CH.sub.3)CO CF.sub.3 CH.sub.3 H,H OH CH.sub.3 OH 1 CO IIIa -- -- --     (CH.sub.2).sub.2 CONH CF.sub.3 CH.sub.3 (CH.sub.2).sub.6 OCH.sub.2     CH.sub.3 CH.sub.3 OH 4 CO IIIb 0 1 -- CH.sub.2 CON.sub.φ Cl H     H,CH.sub.2 CH.sub.3 OH H OCH.sub.3 2 CO IIIc 0 1 -- (CH.sub.2).sub.5     CON(CH.sub.2 CH.sub.2 φ) Cl CH.sub.3 H,H OH CH.sub.3 OH 3 CO IIId 1     1 0 CH.sub.2 CON(CH.sub.2 CH.sub.2 CH.sub.3) Cl H CH.sub.2      CH.sub.3,CH.sub.2 CH.sub.3 OCH.sub.2 CH.sub.3 CH.sub.3 OH 4 SO.sub.2     IIIb 1 0 -- CH.sub.2 CON(CH.sub.2 φ) Cl CH.sub.3 H,CH.sub.2 CH.sub.3     OH CH.sub.3 OH 3 SO.sub.2 IIIb 1 1 -- (CH.sub.2).sub.2 NHCO CF.sub.3     CH.sub.2 CH.sub.3 H,CH.sub.2 φ  OCH.sub.2 CH.sub.3 H OH 2 CO IIIb 2     0 -- (CH.sub.2).sub.6 CON(CH.sub.2 CH.sub.3) Cl H (CH.sub.2).sub.5 OH     (CH.sub.2).sub.4 NH.sub.2 OH 4 CO IIIb 0 2 -- (CH.sub.2).sub.3      N(CH.sub.3)CO CF.sub.3 H H,H OH CH.sub.3 OH 1 SO.sub.2 IIIc 1 0 --     CH.sub.2 CONH Cl CH.sub.3 CH.sub.3,CH.sub.3 OH CH.sub.3 OH 4 SO.sub.2     IIIc 1 1 -- (CH.sub.2).sub.3 N(CH.sub.3)CO Cl CH.sub.3 H,φ OCH.sub.2     CH.sub.3 H OCH.sub.2 CH.sub.3 3 CO IIIc 2 0 -- (CH.sub.2).sub.3      CON(CH.sub.3) Cl H (CH.sub.2).sub.4 OH CH.sub.3 OH 2 CO IIIc 2 1 --     (CH.sub.2).sub.2 N(φ)CO CF.sub.3 CH.sub.3 H,H OH CH.sub.3 OH 4     SO.sub.2 IIId 1 0 0 CH.sub.2 CON(CH.sub.3) Cl H H,H OH H OH 3 CO IIId 1     0 1 (CH.sub.2).sub.3 NHCO Cl CH.sub.3 CH.sub.2 CH.sub.3,CH.sub.2     CH.sub.3 OH CH.sub.3 OCH.sub.2      CH.sub.3 2 SO.sub.2 IIId 2 0 0 (CH.sub.2).sub.3      CONH Cl H H,CH.sub.2,φ OCH.sub.2 CH.sub.3 (CH.sub.2).sub.4 NH.sub.2     OH 3 CO IIId 2 0 1 (CH.sub.2).sub.8 NHCO Cl H H,H OH CH.sub.3 OH     1

The following are non-limiting examples of topical ophthalmicformulations for use in the present invention. The term "Compound A"refers to 1-{N-[1(S)-carboxy-5-[2-(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazin-3-yl)acetamido]pentyl]-(S)-alanyl}-cis,syn-octahydro-1H-indole-2(S)-carboxylic acid. It is contemplated,however, that this compound may be replaced by equally effectivequantities of other compounds within the scope of formulae I or II asdefined above.

EXAMPLE 9

    ______________________________________                                        Topical Solution:                                                             Ingredients         mg/ml                                                     ______________________________________                                        Compound A          10.0                                                      Dibasic Sodium Phosphate                                                                          10.4                                                      Monobasic Sodium Phosphate                                                                        2.4                                                       Chlorobutanol       5.0                                                       Hydroxypropyl methylcelluose                                                                      5.0                                                       Sterile Water       q.s. ad 1.0 mL.                                           1.0N NaOH           q.s. ad pH 7.4                                            ______________________________________                                    

Mix the ingredients under sterile conditions and using standardtechniques to obtain the opthamological solution.

    ______________________________________                                        Topical Solution:                                                             Ingredients         mg/ml                                                     ______________________________________                                        Compound A          0.01                                                      Timolol             1.0                                                       Dibasic Sodium Phosphate                                                                          10.4                                                      Monobasic Sodium Phosphate                                                                        2.4                                                       Chlorobutanol       5.0                                                       Hydroxypropyl methylcelluose                                                                      5.0                                                       Sterile Water       q.s. ad 1.0 mL.                                           1.0N NaOH           q.s. ad pH 7.4                                            ______________________________________                                    

Mix the ingredients under sterile conditions and using standardtechniques to obtain the opthamological solution.

Again, other compounds of formulas I or II could be substituted as wellas other beta blockers, such as labetalol, dilevalol, or betaxolol, withthe amount of the particular drug varying depending upon the IOPreducing activity of the drugs employed.

EXAMPLE 11

    ______________________________________                                        Topical Solution:                                                             Ingredients          mg/ml                                                    ______________________________________                                        Compound A           0.01                                                     Dexamethasone Sodium Phosphate                                                                     1.0                                                      Dibasic Sodium Phosphate                                                                           10.4                                                     Monobasic Sodium Phosphate                                                                         2.4                                                      Chlorobutanol        5.0                                                      Hydroxypropyl methylcelluose                                                                       5.0                                                      Sterile Water        q.s. ad 1 mL.                                            1.0N NaOH            q.s. ad pH 7.4                                           ______________________________________                                    

Mix the ingredients under sterile conditions and using standardtechniques to obtain the opthamological solution.

Again, other compounds of formula I or II and steroidalanti-inflammatory agents such as hydrocortisone, prednisolone,betamethasone, beclomethasone, medrysone, or fluoromethalone can beemployed in place of those listed in the formulation above, theparticular amounts varying depending on the drugs employed.

While the present invention has been described in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand variations thereof will be apparent to those of ordinary skill inthe art. All such alternatives, modifications and variations areintended to fall within the spirit and scope of the present invention.

We claim:
 1. A method for reducing and/or controlling elevatedintraocular pressure in a mammal which comprises topically administeringto an eye of said mammal a composition comprising the combination of ananti-inflammatory amount of an anti-inflammatory steroid an intraocularpressure reducing effective amount of a compound represented by theformulae: ##STR9## or their isomers or pharmaceutically acceptable saltsthereof, in combination with an ophthamologically acceptable carrier fortopical use, wherein ##STR10## R¹ is hydrogen or lower alkyl; R² and R⁵are independently hydrogen, lower alkyl, phenyl, orphenyl(lower)alkyl;R³ and R⁴ are independently hydrogen, lower alkyl,haloloweralkyl, phenyl, or phenyl(lower)alkyl, or R³ and R⁴ takentogether with the carbon to which they are attached can form a 5-7membered cycloalkyl ring; R⁶ and R⁸ are independently hydroxy, alkoxyhaving from 1 to 8 carbon atoms, L--Q_(r) --(CH₂)_(s) --O--, wherein Lis phenyl, substituted phenyl, 1- naphthyl or 2-naphthyl; Q is oxygen orsulfur; r is 0 or 1 and s is 0 to 4; and wherein the substituents on thephenyl are chosen from group M, wherein M is halogen, hydroxy,trifluoromethyl, alkoxy having from 1 to 6 carbon atoms, alkyl from 1 to6 carbon atoms, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl and phenyl(which phenyl group may be substituted with halogen, hydroxy,trifluoromethyl, alkoxy having from 1 to 6 carbon atoms or alkyl havingfrom 1 to 6 carbon atoms); provided that when s is zero, r is zero;--OCH₂ --OCO--alkyl wherein the alkyl has from 3 to 8 carbon atoms,--OCH₂ CO--phenyl, wherein the phenyl may be substituted ##STR11## withgroup M, 1-gylceryl, R⁷ is hydrogen, lower alkyl, or aminoloweralkyl; R⁹is hydrogen, lower alkyl, unsubstituted or substituted phenyl, andsubstituted or unsubstituted phenyl lower alkyl, wherein phenyl may besubstituted by group M; R¹⁰ is hydrogen or lower alkyl; a is 0-8; b is1-8; c is 2-8; m is 1-4; n is 0 or 1; p and q are each 0, 1 or 2,provided that in formulae IIIb and IIIc the sum of p and q is 1 or 2,and that in formulae IIId, p is not
 0. 2. A method according to claim 1wherein R⁶ and R⁸ are both hydroxy.
 3. A method according to claim 1wherein A is --SO₂ --.
 4. A method according to claim 1 wherein A is##STR12##
 5. A method according to claim 1 wherein B is represented byformula IIIa.
 6. A method according to claim 1 wherein B is representedby formula IIIb.
 7. A method according to claim 6 wherein p is 0 and qis
 1. 8. A method according to claim 1 wherein B is represented byformula IIIc.
 9. A method according to claim 8 wherein p and q areeach
 1. 10. A method according to claim 1 wherein B is represented byformula IIId.
 11. A method according to claim 10 wherein p and q areeach 1 and n is zero.
 12. A method according to claim 7 wherein thecompound is 1-{N-[1(S)-ethoxycarbonyl-5-[2-(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazin-3-yl)acetamido]-pentyl]-(S)-alanyl}-cis,syn-octahydroindole-2(S)-carboxylic acid.
 13. A method according toclaim 7 wherein the compound is 1-{(N-[1(S)-carboxy-5-[2-(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazin-3-yl)acetamido]-pentyl]-(S)-alanyl}-cis,syn-octahydroindole-2(S)-carboxylic acid.
 14. A method according toclaim 7 wherein the compound is1-{N-[1(S)-ethoxycarbonyl-4-[2-(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazin-3-yl)acetamido]-butyl]-(S)-alanyl}-cis,syn-octahydroindole-2(S)-carboxylic acid.
 15. A method according toclaim 7 wherein the compound is1-{N-1(S)-carboxy-4-[2-(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazin-3-yl)acetamido]-butyl]-(S)-alanyl}-cis,syn-octahydroindole-2(S)-carboxylic acid.
 16. A method according toclaim 7 wherein the compound is 1-{N-[1(S)-carboxy-5[2-(6-chloro-3, 4dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazin-3-yl)-acetamido]-pentyl]-(S)-alanyl}-cis,syn-octahydroindole-2(S)-carboxylicacid,
 17. A method according to claim 7 wherein the compound is1-{N-[1(S)-carboxy-2-(N-(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazin-3-yl-methyl)-carbamoyl)ethyl]-(S)-alanyl}-cis,syn-octahydroindole-2(S)-carboxylic acid.
 18. Amethod according to claim 7 wherein the compound is1-{N-[1(S)-ethoxycarbonyl-2-(N-(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazin-2-yl-methyl)-carbamoyl)ethyl]-(S)-alanyl)-cis, syn-octahydroindole-2(S)-carboxylic acid.
 19. Amethod according to claim 7 wherein the compound is1-{N-[1(S)-ethoxycarbonyl-2-(N-2-(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazin-2-yl)ethyl)-carbamoyl)-ethyl]-(S)-alanyl}-cis,syn-octahydroindole-2(S)-carboxylic acid.
 20. A method according toclaim 7 wherein the compound is 1-{N-[1(S)-carboxy-2(N-(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazin-2-yl)ethyl)-carbamoyl)-ethyl]-(S)-alanyl}-cis,syn-octahydroindole-2(S)-carboxylic acid.
 21. A method according toclaim 7 wherein the compound is 1-{N-[1(S)-carboxy-2-(N-(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazin-2-yl)methyl)-carbamoyl)-ethyl]-(S)-alanyl}-cis,syn-octahydroindole-2(S)-carboxylic acid.
 22. A method according toclaim 1 wherein the anti-inflammatory steroid is selected fromhydrocortisone, cortisone, prednisolone, prednisone, dexamethasone,methylprednisolone, triamcinolone, betamethasone, fluorometholone,alclometasone, flunisolide, beclomethasone, clorocortolone, diflorasone,halcinonide, fluocinonide, flucinolone, desoximetasone, medrysone,paramethasone or9,21-dichloro-17[(2-furanylcarbonyl)-oxy]-11-hydroxy-16α-methyl-pregna-1,4-diene-3,20-dioneand pharmaceutically acceptable salts, esters, isomers and/or mixturesthereof.
 23. A method according to claim 1 wherein saidanti-inflammatory steroid is administered topically together with acompound of formula I or II in said composition.
 24. A method accordingto claim 23 wherein the anti-inflammatory steroid is selected fromhydrocortisone, cortisone, prednisolone, prednisone, dexamethasone,methylprednisolone, triamcinolone, betamethasone, alclometasone,flunisolide, beclomothasone clorocortolone, diflorasone, halcinonide,fluocinonide, flucinolone, desoximetasone, medrysone, paramethasone,9,21-dichloro-17-[(2-furanylcarboxyl)oxy]-11-hydroxy-16α-methyl-pregna-1,4-diene-3,20-dione, or fluorometholone, or pharmaceutically acceptablesalts, esters, isomers and/or mixtures thereof.
 25. A topicalophthalmologically acceptable composition useful for controlling and/orreducing elevated intraocular pressure which comprises anti-inflammatoryamount of an anti-inflammatory steroid and an intraocular pressurereducing effective amount of a compound of formula I or II as defined inclaim 1 in combination with an ophthalmologically acceptable carrier fortopical use.
 26. A composition according to claim 25 wherein theanti-inflammatory steroid is selected from hydrocortisone, cortisone,prednisolone, prednisone, dexamethasone, methylprednisolone,triamcinolone, betamethasone, alclometasone, flunisolide, beclomothasoneclorocortolone, diflorasone halcinonide, fluocinonide, flucinolone,desoximetasone, medrysone, paramethasone,9,21-dichloro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16α-methyl-pregna-1,4-diene-3,20-dione, orfluorometholone, or pharmaceutically acceptable salts, esters, isomersand/or mixtures thereof.